Desflurane, 2-(difluoromethoxy)-1,1,1,2-tetrafluoroethane, is an inhalation anesthetic possessing very advantageous properties. Desflurane is of significant commercial potential, in particular, as a result of being an effective anesthetic which demonstrates rapid induction and an unexpectedly rapid recovery from anesthesia. The latter property makes it especially attractive for surgical procedures done on an out-patient basis.
Desflurane is disclosed in Example XXI of Russell et al, U.S. Pat. No. 3,897,502, issued Jul. 29, 1975, which is directed to processes for making fluorinated ethers which are useful as solvents to prepare pastes and dispersions of fluorine-containing olefins and fluorowaxes, and as degreasing agents. The use of desflurane as an anesthetic is patented in Terrell, U.S. Pat. No. 4,762,856, issued Aug. 9, 1988.
The development of desflurane, typical of the highly fluorinated, volatile anesthetic ethers known in the art, has been as a racemic mixture since, heretofore, separation into the component enantiomers has not proven feasible and all known syntheses produce the racemic mixture. In fact, there is only a single fluorinated anesthetic for which the separation into optical isomers has been reported in the literature, F. Y. Edamura et al, 159th American Chemical Society National Meeting Orgn. Abstract No. 84, (1970). However, this anesthetic, halothane (CF.sub.3 CHClBr), is not a fluorinated ether. Although the separation of enantiomers of halothane is reported by J. J. Kendig, et al, Anesthesiology, Vol. 39, (1973), p 518, there is no indication given of the optical purity thereof, nor is there any indication that either isomer was ever tested in vivo for pharmacologic activity. Finally, there is no suggestion given that the reported technique would have applicability to fluorinated ether structures.
In accordance with the present invention, a process has been found to synthesize and isolate the optical isomers of desflurane in high optical purity, i.e. in excess of 90 percent optically pure. It has been found that the optical isomers of desflurane, prepared and isolated in high purity, differ significantly in pharmacologic response and that the highly purified positive isomer is unexpectedly advantageous as an inhalation anesthetic.